Cardiovascular Effects of Anti-Diabetic Medications in Type 2 Diabetes Mellitus Authors
Diabetes and Cardiovascular Disease (S Malik, Section Editor)
First Online: 08 December 2012 DOI:
Cite this article as: Singh, S., Bhat, J. & Wang, P.H. Curr Cardiol Rep (2013) 15: 327. doi:10.1007/s11886-012-0327-1 Abstract
Over the past several years, there have been a significant number of new agents developed for the treatment of type 2 diabetes. Our goal in this article is to review the cardiovascular effects (risks and benefits) of these oral and non-insulin injectable agents. We review six major categories of diabetic therapies: biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, GLP-1 agonists, and DPP-IV inhibitors. In order to achieve a personalized regimen that aims for optimal outcomes, we must take into consideration each drug’s side effects, patients’ cardiovascular risk factors, and their individual health profile.
Keywords Type 2 diabetes Medications Side effects Oral agents Heart Cardiovascular effects
This article is part of the Topical Collection on
Diabetes and Cardiovascular Disease References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
National Diabetes Fact Sheet, 2011. Available at
. Accessed 2011.
Hemmignsen B, Lund SS, Wetterslev J, Vaag A. Oral hypoglycemic agents, insulin resistance and cardiovascular disease in patients with type 2 diabetes. Eur J Endocrinol. 2009;161:1–9.
The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.
The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.
• Messaoudi SE, Rongen GA, de Boer RA, Riksen NP. The cardioprotective effects of metformin. Curr Opin Lipidol. 2011;22:445–53.
This is a recent review of myocardial ischemia-reperfusion injury and metformin in animal models.
Palumbo PJ. Metformin: effects on cardiovascular risk factors in patients with non insulin-dependent diabetes mellitus. J Diabetes Complicat. 2008;12:110–9.
Selvin E, Bolen S, Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Int Med. 2008;168:2070–80.
•• Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169:616–25.
This is one of the few randomized controlled trials, as a follow up to the UKPDS, that showed an improvement in macrovascular outcomes when metformin was added to an insulin regimen.
Schramm TK, Gislason GH, Vaag A, et al. Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study. Eur Heart J. 2011;32:1900–8.
Roussel R, Travert F, Pasquet B, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010;170:1892–9.
McAlister FA, Eurich DT, Majumdar SR, Johnson JA, et al. The risk of heart failure in patients with type 2 diabetes treated with oral agent Monotherapy. Eur J Heart Fail. 2008;10:703–8.
Eurich DT, McAlister FA, Balckburn DF, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. Available at bmj.com. Accessed 2007.
Sadikot S, Mogensen CE. Risk of coronary artery disease associated with initial sulfonylurea treatment of patients with type 2 diabetes: a matched case–control study. Diabetes Res Clin Pr. 2008;82:391–5.
Brady PA, Terzic A. The sulfonylurea controversy: more questions from the heart. JACC. 1998;31:950–6.
Evans JMM, Ogston SA, Reimann F, et al. No differences in mortality between users on pancreatic-specific and non-pancreatic specific sulfonylureas: a cohort analysis. Diabetes Obes Metab. 2008;10:350–2.
Pantalone KM, Kattan MW, Yu C, et al. The risk of overall mortality in patients with type 2 diabetes receiving glipizide, glyburide, or glimeperide monotherapy. Diabetes Care. 2010;33:1224–9.
Andersson C, Gislason GH, Jorgensen JH, et al. Comparable long-term mortality risk associated with individual sulfonylureas in diabetes patients with heart failure. Diabetes Res Clin Pr. 2011;94:119–25.
Tomai F, Crea F, Gaspardone A, et al. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K + channel blocker. Circulation. 1994;90:700–5.
Klepzig H, Kober G, Matter C, et al. Sulfonylureas and ischaemic preconditioning: a double-blind placebo controlled evaluation of glimeperide and glibenclamide. Eur Heart J. 1999;20:439–46.
Zeller M, Danchin M, Simon D, et al. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab. 2010;95:4993–5002.
UK Prospective Diabetes Study Group (UKPDS). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 2008;352:853–7.
Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM. A systematic review and meta-analysis of hypoglycemia and cardiovascular events. Diabetes Care. 2007;30:389–94.
• Pantalone KM, et al. Increase in overall mortality risk in patients with type 2 diabetes receiving glipizide, glyburide or glimeperide monotherapy versus metformin: a retrospective analysis. Diabetes Obes Metab. 2012;14:803–9.
A recent large retrospective review that showed an increased mortality with 3 different sulfonylureas compared to metformin.
Evans JMM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia. 2006;49:930–6.
Vameq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet. 1999;354:141–8.
Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, and glyburide monotherapy. N Engl J Med. 2006;355:2427–43.
Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American diabetes association and the European association for the study of diabetes. Diabetes Care. 2006;29:1963–72.
Nesto RW, Bell D. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American heart association and American diabetes association. Circulation. 2003;108:2941–8.
Haffner SM. Epidemiology of hypertension and insulin resistance syndrome. J Hypertens Suppl. 1997;15:S25–30.
Qayyum R, Adomaityte J. A meta-analysis of the effect of thiazolidinediones on blood pressure. J Clin Hypertens. 2006;8:19–28.
Mayerson AB, Hundal RS, Dufour S, et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes. 2002;51:797–802.
Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005;28:1547–54.
Robinson JG. Should we use PPAR agonists to reduce cardiovascular risk? PPAR Res. Article ID. 2008;891425:1–13.
Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone clinical trial in macroVascular events): a randomised controlled trial. Lancet. 2005;366:1279–89.
Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299:1561–73.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.
• Standl E, Schnell O, Alpha-glucosidase inhibitors. Alpha-glucosidase inhibitors 2012 – cardiovascular considerations and trial evaluation. Diabetes Vasc Dis Res. 2012;0:1–7.
A recent review of studies done on the cardiovascular effects of acarbose.
Van de Laar FA, Lucassen PL, Akkerma RP, et al. Alpha-glycosidase inhibitors for patients with type 2 diabetes: results from a Cochrane systematic review and meta-analysis. Diabetes Care. 2005;28:154–63.
• Lin SD, Wang JS, Hsu SR, et al. The beneficial effect of alpha-glucosidase inhibitor on glucose variability compared with sulfonyurea in Taiwanese type 2 diabetic patients inadequately controlled with metformin: preliminary data. J Diabetes Complicat. 2011;25:332–8.
A randomized study that showed the addition of acarbose to metformin causes much lower glucose variability throughout the day compared to the addition of a sulfonylurea, glimeperide.
Suzuki Y, Sano M, Hayashida K, et al. Are the effects of a-glucosidase inhibitors on cardiovascular events related to elevated levels of hydrogen gas in the gastrointestinal tract? FEBS Lett. 2009;583:2157–215.
Kajiyama S, Hasegawa G, Asano M, et al. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res. 2008;28:137–43.
Chiasson J, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072–7.
Chiasson J, Josse RG, Gomis R, et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486–94.
Hanefeld M, Chiasson JL, Koehler C, et al. Acarbose slows progression of intima-media thickness of the carotid arteries in subjects with impaired glucose tolerance. Stroke. 2004;35:1073–8.
Hanefeld M, Cagatay M, Petrowitsch T. Acarbose reduces the risk of myocardial infarction in type 2 diabetics: meta-analysis of seven long-term studies. Eur Heart J. 2004;25:10–6.
Rosenthal JH, Mauersberger H. Effects on blood pressure of the alpha-glucosidase inhibitor acarbose compared with the insulin enhancer glibenclamide in patients with hypertension and type 2 diabetes mellitus. Clin Drug Invest. 2002;22:695–701.
Esposito K, Ciotola M, Carleo D, et al. Post-meal glucose peaks at home associate with carotid intima-media thickness in type 2 diabetes. J Clin Endocrinol Metab. 2008;93:1345–50.
Schisano B, Tripathi G, McGee K, et al. Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells. Diabetologia. 2011;54:1219–26.
Hanefeld M, Fischer S, Schulze J, et al. Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care. 1991;14:732–7.
Satoh N, Shimatsu A, Yamada K, et al. An a-glucosidase inhibitor, voglibose, reduces oxidative stress markers and soluble intercellular adhesion molecule 1 in obese type 2 diabetic patients. Metabolism. 2006;55:786–7.
Yokoyama H, Kannno S, Ishimura I, et al. Miglitol increases the adiponectin level and decreases urinary albumin excretion in patients with type 2 diabetes mellitus. Metabolism. 2007;56:1458–63.
Kim W, Egan J. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60:470–512.
Chia CW, Egan JM. Incretin-based therapies in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2008;93:3703–16.
Ahren B, Landin-Olsson M, Jansson P, et al. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab. 2004;89:2078–84.
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705.
•• Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366:1577–85.
Important article demonstrating how significantly different diabetes outcomes are in patients who undergo bariatric surgery versus medical treatment of diabetes. This could potentially change the stringent requirements patients have to meet in order to qualify for bariatric surgery.
Horton ES, Silberman C, Davis KL, Berria R. Weight loss, glycemic control, and changes in cardiovascular biomarkers in patients with type 2 diabetes receiving incretin therapies or insulin in a large cohort database. Diabetes Care. 2010;33:1759–63.
Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275–86.
• Addison D, Aguilar D. Diabetes and cardiovascular disease: the potential benefit of incretin-based therapies. Curr Atheroscler Rep. 2011;13:115–22.
Review article describing benefits of incretin therapies in treatment of cardiovascular disease.
Forst T, Weber MM, Pfutzner A. Cardiovascular benefits of GLP-1 based therapies in patients with diabetes mellitus type 2: effects on endothelial and vascular dysfunction beyond glycemic control. Exp Diabetes Res. 2012;2012:1–9.
Courreges JP, Vilsbollt T, Zdravkovic M, et al. Beneficial effects of once-daily liraglutide, a human glucagon like peptide-1 analogue, on cardiovascular risk biomarkers in patients with type 2 diabetes. Diabetic Med. 2008;25:1129–31.
Best JH, Hoogwerf BJ, Herman WH, et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist Exenatide twice daily or other glucose-lowering therapies. A retrospective analysis of the LifeLink database. Diabetes Care. 2011;34:90–5.
Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010;122:16–27.
Bethel MA, Green J, Califf RM, Holman RR. Rationale and design of the trial evaluating cardiovascular outcomes with sitagliptin (TECOS). Diabetes. 2009;58:A639.
© Springer Science+Business Media New York 2012